Integration of 111 reference human epigenomes helps interpret the molecular basis of complex traits and disease. M. Kellis, C. Roadmap Epigenomics Computer Science, Broad Institute, MIT & Harvard, Cambridge, MA.

   The NIH Roadmap Epigenomics Consortium generated the largest collection to-date of human epigenomes for primary cells and tissues. Here, we undertake an integrative analysis of 111 reference human epigenomes profiled for histone modification patterns, chromatin accessibility, DNA methylation, and RNA expression. We establish global maps of regulatory elements, define enhancer modules of coordinated activity, and infer regulatory networks linking enhancers to regulators and target genes. We study DNA methylation across chromatin states, cell types, and during differentiation, and the epigenomic signatures that distinguish age, sex, and lineage specification. We find that epigenetic features at enhancer regions are highly dynamic features across tissues, individuals, genotypes, and disease state, in contrast to mostly invariant features at promoters. We use epigenomic information to predict pathways harboring regulatory variants associated with complex traits, to identify disease-relevant cell types and regulators, and to determine the tissue-of-origin of cancer samples. Lastly, we use model organisms to support the biological relevance of sequence variants with associations below genome-wide significance but lying in relevant epigenomic states in Alzheimers and cardiac phenotypes. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation, and human disease.

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